title: Periconceptional folic acid associated with an increased risk of oral clefts relative to non-folate related malformations in the Northern Netherlands: a population based case-control study.
abstract: Periconceptional folic acid has been associated with a reduced risk of neural tube defects, but findings on its effect in oral clefts are largely inconclusive. This case-control study assesses the effects of periconceptional folic acid on cleft risk, using complementary data from the Dutch Oral Cleft Registry and a population-based birth defects registry (Eurocat) of children and foetuses born in the Northern Netherlands between 1997 and 2009. Cases were live-born infants with non-syndromic clefts (n = 367) and controls were infants or foetuses with chromosomal/syndromal (n = 924) or non-folate related anomalies (n = 2,021). We analyzed type/timing/duration of supplement use related to traditional cleft categories as well as to their timing (early/late embryonic periods) and underlying embryological processes (fusion/differentiation defects). Consistent supplement use during the aetiologically relevant period (weeks 0-12 postconception) was associated with an increased risk of clefts (adjusted odds ratio 1.72, 95% confidence interval 1.19-2.49), especially of cleft lip/alveolus (3.16, 1.69-5.91). Further analysis systematically showed twofold to threefold increased risks for late differentiation defects-mainly clefts of the lip/alveolus-with no significant associations for early/late fusion defects. Effects were attributable to folic acid and not to other multivitamin components, and inclusion of partial use (not covering the complete aetiologically relevant period) generally weakened associations. In conclusion, this study presents several lines of evidence indicating that periconceptional folic acid in the Northern Netherlands is associated with an increased risk of clefts, in particular of cleft lip/alveolus. This association is strengthened by the specificity, consistency, systematic pattern, and duration of exposure-response relationship of our findings, underlining the need to evaluate public health strategies regarding folic acid and to further investigate potential adverse effects.
authors.affiliation: Department of Plastic and Reconstructive Surgery, Erasmus MC, University Medical Center Rotterdam, Room EE 1591, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands, am.rozendaal@gmail.com.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Rozendaal
authors.forename: Anthonie J
authors.initials: AJ
authors.lastname: van Essen
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: te Meerman
authors.forename: Marian K
authors.initials: MK
authors.lastname: Bakker
authors.forename: Jan J
authors.initials: JJ
authors.lastname: van der Biezen
authors.forename: Sieneke M
authors.initials: SM
authors.lastname: Goorhuis-Brouwer
authors.forename: Christl
authors.initials: C
authors.lastname: Vermeij-Keers
authors.forename: Hermien E K
authors.initials: HE
authors.lastname: de Walle
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002971:Cleft Lip / Q000453:epidemiology / Q000517:prevention & control*; D002972:Cleft Palate / Q000453:epidemiology / Q000517:prevention & control*; D016001:Confidence Intervals; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008297:Male; D008423:Maternal Age; D015999:Multivariate Analysis; D009426:Netherlands / Q000453:epidemiology; D016017:Odds Ratio; D011159:Population Surveillance; D011247:Pregnancy; D012306:Risk; D012307:Risk Factors; D012959:Socioeconomic Factors; D013997:Time Factors; D014803:Vitamin B Complex / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
chemical_list: D014803:Vitamin B Complex; D005492:Folic Acid